Jacob Hanna

During his postdoctoral research at the Whitehead Institute, Hanna focused on studying embryonic stem cells (ESCs) and epigenetic reprogramming of somatic cells into ESC-like cells, called induced pluripotent stem cells (iPSCs). He developed transgenic mouse models to address problems in stem cell research. In 2007, he utilized his previous clinical knowledge and Ph.D. training in immunology to provide the first evidence that iPSCs could be used for blood genetic disease (like sickle cell anemia) by combined gene and cell therapy approach in mice.[22] His supervisor, Jaenisch was awarded the Masri Prize and the Wolf Prize in 2011 for this research innovation, as the citation read: "For demonstration that iPS cells can be used to cure genetic disease in a mammal, thus establishing their therapeutic potential".[23]

Hanna made scientific contributions to understanding the iPSC phenomenon in its early days. He developed a novel doxycycline-inducible "reprogrammable mouse" transgenic models with drug controlled over expression of the Yamanaka reprogramming factors. This technique allowed him to create reprogrammed B lymphocytes carrying endogenous genetic rearrangements of the B-cell receptor (BCR) into iPSCs, thus providing definitive proof for the feasibility of reprogramming terminally differentiated B cells to iPSCs that carried the original genetic rearrangement mark of the BCR.[24]

With scientists at the Broad Institute and Harvard, Hanna utilized this reprogrammable mouse system to conduct the first in depth integrative epigenomic analysis of reprogramming to pluripotency and elucidated the role of DNA methylation as a barrier for re-establishing pluripotency.[25] Hanna, with a team of physicists at MIT, provided the first theoretical and mathematical descriptions of canonical iPS reprogramming[13] (introducing Oct4, Sox2, Klf4 and c-Myc reprogramming factors as originally described by Shinya Yamanaka) as a stochastic process with as low as only one rate limiting step, and that stochastic iPS formation efficiency can be directly increased by accelerating cell proliferation rate.[13]

In April 2011, Hanna joined the Department of Molecular Genetics at the Weizmann Institute of Science in Israel as an Assistant Professor, and has been an independent group leader there ever since.[15] He was awarded promotion with tenure at the Weizmann Institute in 2018,[14] and set up his laboratory for "Pluripotent Stem Cell Studies & Ex Utero Embryogenesis".[26]

Initially, his group identified a number of key epigenetic regulators influencing iPSC derivation efficiency such as the role of H3K27 demethylase Utx in iPS formation,[27] and first demonstrated the deterministic reprogramming efficiencies (up to 100% within 8 days) via optimized depletion of Gatad2a/Mbd3 core member-axis of the NuRD co-repressor complex.[28][29] The latter work set the stage for others to show alternative methods to obtain deterministic reprogramming. For example, Thomas Graf group showed that transient activation of C/EBPα, previously highlighted by Hanna and Jaenisch as a booster for B cell reprogramming,[30] can yield up to 100% deterministic iPSC reprogramming from B cells within 8 days.[31] Hanna also identified SUMOylation of linker H1 histone[32] as a major determinant for transition between totipotency and naïve pluripotency states.

The Hanna team has also tackled pathways that resolve naive pluripotency programs and delineated a critical function for m⁶A RNA methylation in stem cell transitions in peri-implantation mouse development. Their study published in Science in 2015[33] provided the first evidence for the absolute essentiality of m6A mRNA epigenetic layer for mammalian embryo viability in vivo[33] and uncovered opposing tolerance of epigenetic repressor depletion in naive and primed cells from the same species,[33] that Hanna later used to optimize naive conditions in humans since only naive cells can tolerate genetic ablation or RNA and DNA methylation (deposited and maintained by METTL3 and DNMT1 enzymes, respectively).[34] Hanna used the latter property to screen for conditions that allow survival of human pluripotent cells without these enzymes and termed the conditions human enhanced naive stem cell media (HENSM).[34]

Hanna's lab also focused on deciphering the principles regulating naive pluripotency in different species and his team was the first to derive human genetically unmodified MEK/ERK independent naïve-like pluripotent cells (termed NHSM conditions that were commercialized as RSeT by Stemcell Technologies).[35] Hanna next developed engineered systems to screen for enhanced NHSM conditions that maintain human pluripotent ES cells that can tolerate removal of RNA or DNA methylation enzymes (by ablating METTL3 or DNMT1 genes, respectively), and identified enhanced NHSM conditions (termed HENSM),[34] that can yield ESCs/iPSCs with more compelling characteristics of human pre-implantation blastocyst-morula stages.

From 2013, Hanna worked as the Robertson Stem Cell Investigator of The New York Stem Cell Foundation.[36] His first major achievement under the NYSCF research was the demonstration that human naïve-like ES/iPS cell state tin NHSM conditions that he discovered (and later also in HENSM conditions), has additional unique functional properties compared to conventional primed iPS cells, which is the creation of sperm and egg stem cells from human skin cell derived naive-like iPSC,[37] which has not been possible thus far with conventional human iPSCs. The experiment, done in collaboration with Azim Surani's team at the University of Cambridge, was published in the journal Cell in 2015.[38] David Cyranoski reported in Nature as "A feat achieved for the first time in humans".[39]

Hanna is most recognized for developing a method for extended culturing of advanced mouse embryos outside the uterus (ex utero) in 2021,[40][41][42] subsequently allowing him to make the first synthetic advanced "organ-filled" mouse embryos derived only from naïve stem cells in 2022.[43][44][45][46] In September 2023, Nature accepted Hanna's, previously preprinted article on bioRxiv on 14 June 2023,[47] on the generation of complete and structured day-14 synthetic human embryos derived from human naïve ES/iPS cells grown in his HENSM conditions.[34][48] Hanna's complete human stem cell-derived embryo model (SEM) can generate extra-embryonic trophoblast stem cells, mesoderm cells and primitive endoderm cells without genetic modification, transgene or transcription factor over-expression, and has structural and morphological uncanny similarity to day 14 human embryo inside the womb.[48][49][50][51] Conventional human (and mouse) primed ES/iPSCs fail to achieve this feat, highlighting the essentiality of capturing alternative naive pluripotent states in humans to be able to derive up to day 14 human SEMs.[48]

Prof Alfonso Martinez Arias, from the department of experimental and health sciences at Pompeu Fabra University, said it was "a most important piece of research". "The work has, for the first time, achieved a faithful construction of the complete structure [of a human embryo] from stem cells" in the lab, "thus opening the door for studies of the events that lead to the formation of the human body plan," Martinez-Arias said.[51] It was reported by Philip Ball that Dr. Bailey Weatherbee from the University of Cambridge who tried to generate human embryo models "is impressed by the embryo-like structures reported by Hanna's team, and agrees that their own don't have these structures."[52] Prof Robin Lovell Badge, who researches embryo development at the Francis Crick Institute, told the BBC that Hanna's human embryo models "do look pretty good" and "do look pretty normal". He also said "I think it's good, I thinks it's done very well, it's all making sense and I'm pretty impressed with it".[51]

Hanna had been accused in 2014 on PubPeer of data misrepresentation in some of his earlier research papers published between 2004 and 2005.[20] Among the earliest accusations was image reuse in previously published images. Hanna's paper with his supervisor Mandelboim on NK cells was published in the journal Blood in 2005[53] and PubPeer comments alleged that several images appeared duplicated from Hanna's paper in the Journal of Clinical Investigation published a year before.[54][55] Hanna responded to Retraction Watch that he will "correct the unfortunate and inadvertent mistakes in due course and ASAP."[20] Hanna explained: "In brief, Figures 4,5,6 and 7 in the blood Manuscript were conducted and assembled by medical trainees (M.D., S.H. and N.W.) based on my instructions while I was away for 6 months at Mount Sinai NYC (end of 2004) for a medical student exchange program. Unfortunately, this led to mistakes in data presentation and use of wrong files, which i still take full responsibility for as their supervisor and first author of the paper. This also relates to mistakes in my 2004 JCI and JI papers, revised during the same period (Corrections for the latter have been submitted and accepted).[56] He published the corrected versions soon afterwards in 2015.[55] After being notified directly by Hanna, the JCI editors decided in 2015 that the errors were too big to be ignored or corrected, and retracted the paper which was published 11 years earlier (in 2004) with a statement: "the original data for this article are no longer available, and it is evident that a number of serious mistakes were made in the preparation of this article. Thus, the JCI editorial board is retracting this article due to the numerous errors in data reporting, misrepresentation of data, and image duplication."[57] The retraction note did not state data manipulation or scientific misconduct accusations against any of the authors.[57] Out of over 130 papers published on which Hanna is an author,[58] 10 have a correction (mostly minor),[59] on half of which Hanna was merely a middle author[60] or the correction resulted from failure of his mentor Rudolf Jaenisch, but not Hanna, to declare his financial conflicts of interest on multiple papers.[61]

In 2014, Hanna criticized Jaenisch, his mentor at the Whitehead Institute, accusing his team of unreliable experimental results. Jaenisch and his team had published a paper on the pluripotency of human embryonic stem cells in the journal Cell Stem Cell.[62] After a discussion on PubPeer,[63] Jaenisch published a correction in the same journal.[64] In 2016, Jaenisch and his team reported in the Proceedings of the National Academy of Sciences a creation of chimeric embryo from a mixture of mouse and human cells.[65] Hanna again gave critical comments in PubMed, suggesting retraction of a section of the previous paper in Cell Stem Cell.[62] However, Jaenisch continues to be invited as a speaker in meetings organized by Hanna (last one in 2023),[66] refuting rumors of personal fallout as claimed by bloggers. PubMed commenting feature was later canceled, and as a result all comments ever posted on PubMed were removed.[67]

In 2022, when Hanna published the mouse synthetic embryo, he reported to the MIT Technology Review that he was already using the same method to make human embryos. The funder company, NFX, stated that the aim is "renewing humanity—making all of us young and healthy."[68] The MIT Technology Review reporter Antonio Regalado criticized the project, saying, "In a next set of experiments, Hanna is using his own blood or skin cells (and those of a few other volunteers) as the starting point for making synthetic human embryos. It means his lab could soon be swimming in hundreds or thousands of tiny mini-mes [referring to the fictional clone of Austin Powers]—all genetic clones of himself." Nicolas Rivron, developmental biologist at the Austrian Academy of Sciences, remarked, "Its absolutely not necessary, so why would you do it?" and argued that scientists should only create "the minimal embryonic structure necessary".[68]

When Hanna announced the creation of human synthetic embryo in a preprinted manuscript on bioRxiv [47] and shortly after in Nature,[48] it was received as a "breakthrough"[69] and "groundbreaking advance" in science.[70] But Hanna's scientific feat raised further the discussions surrounding ethical and legal controversies.[71][72] The International Society for Stem Cell Research (ISSCR) has instituted guidelines for maintaining human embryos that are followed in most countries.[73] However, the guidelines or any other legislations do not cover synthetic embryos,[74] as the embryos are made from ordinary cells.[49] Hanna commented on Stat: "You don't ban nuclear physics because somebody can make a nuclear bomb."[75]

Rivron, Martinez Arias and others, writing on the ethical issues in Cell in 2023, expressed a possible need to open discussions about revising the definition of an embryo since the embryo models can theoretically become functional embryos and produce babies.[74][76] Robin Lovell-Badge, at the Francis Crick Institute and member of the ISSCR guidelines preparation, also agreed that both natural and synthetic human embryos should be regulated equally, saying, "These models do challenge the need to stick to the 14-day rule", referring the ISSCR's relaxation in 2021 the limit of growing human embryos up to 14 days.[73][72] The scientific and ethical complexity were remarked by J. Benjamin Hurlbut, bioethicist at the Arizona State University: "The big question is how the boundary between a tissue culture and a human organism is going to be drawn and on what criteria."[49] Pompeu Fabra University Professor Alfonso Martinez Arias, Ph.D., whose own lab is working on building human embryo models, noted that such conversations and debates are nothing new.[77]

The International Society for Stem Cell Research publicly announced support for the research[78] and British science writer, Philip Ball, alleviated concern related to this line of research by emphasizing that "None [of the embryo model] has the potential to grow into a human being, nor is there any reason why scientists would want them to."[79] Upon publication of Hanna's ground breaking paper on human complete stem cell-derived embryo models (termed SEMs) in Nature in 2023[48] Philip Ball tweeted "This is work at the absolute forefront of this extraordinary and exciting field".[80]